Synergistic protection of nascent DNA at stalled forks by MSANTD4 and BRCA1/2-RAD51

  • Nat Chem Biol. 2025 Jan 14. doi: 10.1038/s41589-024-01833-9.
Haihua Xie  #  1  2  3 ,  Lizhi Song  #  4  5 ,  Genxiang Mao  3 ,  Jinhua Han  3 ,  Jiali Pu  6 ,  Zhibing Wu  3 ,  Jun Chen  3 ,  Jianwei Zhou  1 ,  Jun Huang  7  8  9 ,  Dong Fang  10 ,  Ting Liu  11  12  13
Affiliations
  • 1. Department of Gynecology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 2. Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou, China.
  • 3. Zhejiang Key Laboratory of Geriatrics and Geriatrics Institute of Zhejiang Province, Affiliated Zhejiang Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 4. MOE Laboratory of Biosystems Homeostasis and Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, China.
  • 5. Center for Life Sciences, Shaoxing Institute, Zhejiang University, Shaoxing, China.
  • 6. Department of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 7. Zhejiang Key Laboratory of Geriatrics and Geriatrics Institute of Zhejiang Province, Affiliated Zhejiang Hospital, Zhejiang University School of Medicine, Hangzhou, China. [email protected].
  • 8. MOE Laboratory of Biosystems Homeostasis and Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, China. [email protected].
  • 9. Center for Life Sciences, Shaoxing Institute, Zhejiang University, Shaoxing, China. [email protected].
  • 10. MOE Laboratory of Biosystems Homeostasis and Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, China. [email protected].
  • 11. Department of Gynecology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. [email protected].
  • 12. Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou, China. [email protected].
  • 13. Zhejiang Key Laboratory of Geriatrics and Geriatrics Institute of Zhejiang Province, Affiliated Zhejiang Hospital, Zhejiang University School of Medicine, Hangzhou, China. [email protected].
  • # Contributed equally.
PMID: 39809895 DOI: 10.1038/s41589-024-01833-9
Abstract

The regressed arms of reversed replication forks exhibit structural similarities to one-ended double-stranded breaks and need to be protected against uncontrolled nucleolytic degradation. Here, we identify MSANTD4 (Myb/SANT-like DNA-binding domain-containing protein 4), a functionally uncharacterized protein that uniquely counters the replication protein A (RPA)-Bloom (BLM)/Werner syndrome helicase (WRN)-DNA replication helicase/nuclease 2 (DNA2) complex to safeguard reversed replication forks from detrimental degradation, independently of the breast Cancer susceptibility proteins (BRCA1/2)-DNA repair protein RAD51 pathway. MSANTD4 specifically interacts with the junctions between single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) in DNA substrates harboring a 3' overhang, which resemble the structural features of regressed arms processed by WRN-DNA2. This DNA-binding capability allows MSANTD4 to accumulate at reversed forks, strategically antagonizing the RPA-BLM/WRN-DNA2 complex by impeding its access to the ssDNA-dsDNA junction of the regressed arms. Loss of MSANTD4 exacerbates genome instability induced by replication stress in BRCA1/2-deficient cells. Our findings unveil a collaborative defense mechanism orchestrated by MSANTD4 and BRCA1/2-RAD51, effectively counteracting nucleolytic attacks on the regressed arms and synergistically preserving the integrity of reversed forks.

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